Infection with hepatitis C virus (HCV) results in persistent liver disease in the majority of infected individuals and HCV-associated end-stage liver disease is now the leading indication for liver transplantation in the United States. Many studies have highlighted the importance of the T cell response for viral clearance and attributed persistent infection to an insufficient T cell response. However, in persistent HCV infection the factors leading to immune failure are not clear. We recently published work showing that the intrahepatic HCV-specific T cell response in chronically infected human patients does not mirror the response in the peripheral blood and that, in fact, phenotypically exhausted T cells characterize the liver infiltrating population. Accordingly, we postulate that in the natural course of HCV infection, viral persistence is a direct result of the inadequacy of the intrahepatic immune response and more specifically, that intrahepatic antigen presenting cells (APCs) modulate and impair the antiviral T cell response thereby contributing to viral persistence. Hepatic stellate cells (HSC) are a novel population of intrahepatic APC that undergo dramatic phenotypic and functional changes in response to liver injury or infection. This process is known to be important for liver fibrogenesis, but little is known of the importance of HSC as APCs and how APC function is changed during HCV infection. Our preliminary work indicates a transition from immunostimulatory to immunoinhibitory function upon activation of HSC. Thus, the work proposed here will focus on HSC and their ability to modulate T cell immunity through viral antigen presentation in the context of costimulatory or coinhibitory molecules and the influence that HCV has on this process. We will dissect the pair-wise relationships between HSC and T cells, HSC and HCV, while bringing together all three factors to determine the impact of this tripartite interaction on the outcome of HCV infection. We expect to find that HSC play a role in the intrahepatic T cell dysfunction during HCV infection and therefore promote persistent infection. PUBLIC HEALTH RELEVANCE: Hepatitis C virus (HCV)-induced chronic liver disease with associated cirrhosis and hepatocellular carcinoma is now the leading indication for liver transplantation in the United States. There are currently an estimated 170 million HCV carriers worldwide and nearly 3 million in the U.S. (~2% of the population). We are seeking to elucidate and understand the mechanisms by which the host immune response fails in the majority of those infected and to future efforts to develop prophylactic and/or therapeutic HCV eradication strategies.